How did a patient who types for HLA-B*4403 develop antibodies that react with HLA-B*4402?

This case report shows that the sensitization of a HLA-B*4403 patient by a kidney transplant with a HLA-Cw*0704 mismatch led to antibodies reacting with the 156DA eplet shared with B*4402 and other HLA-B antigens including B*0801, B*3701, B*4101, B*4201, B*4501, and B*8201. It demonstrates that antibodies induced by an HLA-C mismatch can render certain HLA-B antigens unacceptable mismatches although the patient has never been exposed to them. This finding illustrates the importance of analyzing antibody specificities against HLA epitopes in the determination of mismatch acceptability for sensitized patients.

Retransplant candidates have donor-specific antibodies that react with structurally defined HLA-DR,DQ,DP epitopes.

This report describes a detailed analysis how donor-specific HLA class II epitope mismatching affects antibody reactivity patterns in 75 solid organ transplant recipients with an in situ allograft and who were considered for retransplantation. Sera were tested for antibodies in a sensitive antigen-binding assay (Luminex) with single class II alleles. Their reactivity was analyzed with HLAMatchmaker, a structural matching algorithm that considers so-called eplets to define epitopes recognized by antibodies. Only 24% of the patients showed donor-specific anti-DRB1 antibodies and there was a significant correlation with a low number of mismatched DRB1 eplets. This low detection rate of anti-DRB1 antibodies may also be due to allograft absorption. In contrast, antibodies to DRB3/4/5 mismatches were more common. Especially, 83% of the DRB4 (DR53) mismatches resulted in detectable antibodies against an eplet uniquely found on DR53 antigens. Donor-specific DQB mismatches led to detectable anti-DQB antibodies with a frequency of 87%. Their specificity correlated with eplets uniquely found on DQ1-4. The incidence of antibodies induced by 2-digit DQA mismatches was 64% and several eplets appeared to play a dominant role. These findings suggest that both alpha and beta chains of HLA-DQ heterodimers have immunogenic epitopes that can elicit specific antibodies. About one-third of the sera had anti-DP antibodies; they reacted primarily with two DPB eplets and an allelic pair of DPA eplets. These data demonstrate that HLA class II reactive sera display distinct specificity patterns associated with structurally defined epitopes on different HLA-D alleles.

Serum analysis after transplant nephrectomy reveals restricted antibody specificity patterns against structurally defined HLA class I mismatches.

This study deals with HLA-mismatched kidney transplants that have been removed following rejection. Sera from 27 patients were screened for HLA-specific antibodies by direct complement-dependent lymphocytotoxicity with HLA-typed cell panels. Circulating donor-specific antibodies were detected in 3 cases (11%) before and in 26 cases (97%) after allograft nephrectomy. These findings demonstrate the production of donor-specific antibodies in patients with rejected transplants, but in most cases, they were undetectable before nephrectomy, because the graft had adsorbed them. With an HLAMatchmaker-based serum analysis program, we observed restricted antibody specificity patterns against amino acid triplet-defined epitopes on donor HLA-A,B antigens. Many donor triplets were non-reactive while others were apparently recognized by antibodies. In some patients, the donor triplet specific antibodies persisted for a long time whereas in many other patients, they became undetectable after a few months. The characterization of the antibody specificity profiles of post-allograft nephrectomy sera is clinically useful in defining criteria of HLA mismatch acceptability for sensitized patients awaiting another transplant. It provides also opportunities for determining the relative immunogenicity of mismatched triplets.

HLAmatchmaker: a molecularly based algorithm for histocompatibility determination. IV. An alternative strategy to increase the number of compatible donors for highly sensitized patients.

BACKGROUND: HLAMatchmaker is a computer algorithm that determines human leukocyte antigen (HLA) compatibility at the level of polymorphic amino acid triplets in antibody-accessible sequence positions. Recent studies have shown that HLA-DR-matched kidney transplant recipients with zero to two triplet mismatches had almost identical graft survival rates as those with zero HLA-A,B,DR antigen mismatches. This report describes how HLAMatchmaker can be used to identify more compatible donors for highly sensitized patients. METHODS: The HLAMatchmaker program was used to calculate the probability of finding a donor (PFD) with zero, one, or two triplet mismatches for 54 highly sensitized patients waiting for a kidney transplant and having panel reactive antibody (PRA) values greater than 85% and 50 randomly selected nonsensitized patients with PRA values less than 3%. RESULTS: There was a wide variability for PFD values for the two patient cohorts. If only donors with zero HLA-A,B mismatches were deemed acceptable for recipients, the median PFD of a zero-antigen mismatch was 0.046% for nonsensitized patients and 0.009% for highly sensitized patients (P=0.007). Half of the highly sensitized patients had a PFD below 0.01%, or fewer than 1 in 10,000 donors would have zero antigen mismatches. Application of HLAMatchmaker identified additional HLA antigens with zero-triplet mismatches for 27 patients, resulting in a 1.8-fold increase in PFD. Considering additional antigens with one-triplet or two-triplet mismatches increased the PFD by an additional 3.8-fold and 13.7-fold, respectively. Acceptable antigen mismatches for 37 of the 54 highly sensitized patients were identified by consistently negative reactions in serum screens, and their addition resulted in a 12.7-fold increase of the PFD to a median of 0.141%. Applying these acceptable antigens to the HLAMatchmaker algorithm identified additional antigens with zero or acceptable triplet mismatches and their inclusion increased the PFD by 3.3-fold to 0.347%. CONCLUSIONS: HLAMatchmaker offers a valuable strategy for identifying more suitably HLA-matched donors and has the potential for alleviating the problem of accumulation of highly sensitized patients on the transplant waiting list.